The matrix metalloproteinases (MMPs) are a family of zinc endoproteinases, collectively capable of degrading the array of proteins, glycoproteins, and proteoglycans that make up the extracellular matrix. MMPs thus play a critical role in tissue remodeling during normal physiological processes such as wound healing, bone remodeling, and embryonic development. However, overactivity of matrix metalloproteinases is associated with a variety of disease states, including inflammation and caner, making these enzymes attractive targets for therapeutic intervention. Indeed, MMP inhibitors have undergone clinical evaluation for the treatment of caner, with some promising results. In this application, we present preliminary data for a novel class of MMP inhibitors and propose studies directed toward the design and optimization of these compounds, with the aim of identifying a potent, orally active inhibitor for preclinical and clinical development during Phase II of the project. Structure-assisted design, involving the combined use of crystallographic and molecular modeling techniques, as well as combinatorial chemistry and conventional medicinal chemistry, all contribute key element to our integrated design strategy. PROPOSED COMMERCIAL APPLICATION: The primary goal of this project is to identify new and effective agents for the treatment of cancer. Any drug developed as a result of this work may find additional application in the treatment of osteoarthritis, rheumatoid arthritis, and other diseases in which MMPs play a critical role.